Microglia and Interleukin-1β in Ischemic Retinopathy Elicit Microvascular Degeneration Through Neuronal Semaphorin-3A

作者：José Carlos Rivera, Nicholas Sitaras, Baraa Noueihed, David Hamel, Ankush Madaan, Tianwei Ellen Zhou, Jean‐Claude Honoré, Christiane Quiniou, Jean‐Sébastien Joyal, Pierre Hardy, Florian Sennlaub, William D. Lubell, Sylvain Chemtob · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2013 · DOI：10.1161/atvbaha.113.301331 · 被引用次数：146 · 研究领域：Axon Guidance and Neuronal Signaling、Neuroinflammation and Neurodegeneration Mechanisms、Retinal Diseases and Treatments

OBJECTIVE: Proinflammatory cytokines contribute to the development of retinal vasculopathies. However, the role of these factors and the mechanisms by which they elicit their effects in retina are not known. We investigated whether activated microglia during early stages of ischemic retinopathy produces excessive interleukin-1β (IL-1β), which elicits retinal microvascular degeneration not directly but rather by triggering the release of the proapoptotic/repulsive factor semaphorin-3A (Sema3A) from neurons. APPROACH AND RESULTS: Sprague Dawley rats subjected to retinopathy induced by hyperoxia (80% O2; O2-induced retinopathy) exhibited retinal vaso-obliteration associated with microglial activation, NLRP3 upregulation, and IL-1β and Sema3A release; IL-1β was mostly generated by microglia. Intraperitoneal administration of IL-1 receptor antagonists (Kineret, or rytvela [101.10]) decreased these effects and enhanced retinal revascularization; knockdown of Sema3A resulted in microvessel preservation and, conversely, administration of IL-1β caused vaso-obliteration. In vitro, IL-1β derived from activated primary microglial cells, cultured under hyperoxia, stimulated the release of Sema3A in retinal ganglion cells-5, which in turn induced apoptosis of microvascular endothelium; antagonism of IL-1 receptor decreased microglial activation and on retinal ganglion cells-5 abolished the release of Sema3A inhibiting ensuing endothelial cell apoptosis. IL-1β was not directly cytotoxic to ...